Human immunodeficiency viruses (HIVs) may comprise a spectrum of humanretroviruses with varied potential for latency, virulence and pathogenicity. These capacities may be governed, in part, by their genetic structure. This project aims to gain an understanding of pathogenicity by analyzing the structure and function of the genomes of the highly pathogenic (HIV- 2[ROD]) and weakly or nonpathogenic (HIV-2[ST]) HIVs. Since much of the virus regulation is centered in its long terminal repeat (LTR), relevant to latency and virulence, and the envelope gene plays a major role in pathogenicity, the focus of this study is the LTR-based regulatory elements and regulatory genes (tat), and the envelope gene. Also relevant are the properties of these viruses to be activated by cofactors, e.g., T cell activation. We recently described the novel observation that sequence elements downstream of the transcriptional initiation site in the HIV-2 LTR down-modulate viral gene expression. A study mapping the functional domain of HIV-2 Tat by mutational analysis revealed several important domains. In addition to the cysteine- and arginine-rich domains, it contains a domain just upstream and another just downstream of the cysteine-rich domain which is important for HIV-2 as well as HIV-1 LTR transactivation. Evaluation of a battery of HIV-2 Tat mutants did not reveal a potent transdominant negative Tat. This included Tats which would be analogs of HIV-1 Tat transdominant mutants, suggesting mechanistic differences between HIV-1 and HIV-2 transactivation. Mapping of the determinants of HIV-2 fusiogenicity and cytopathicity by the analysis of a series of chimeric provirus between noncytopathic HIV-2(ST) and cytopathic HIV-2(ROD) revealed envelope to be a major factor. However, no single linear domain within the envelope, including the major CD4 binding or fusion domain, was a sufficient determinant of fusiogenicity, implicating the involvement of multiple and discontinuous epitopes. Neither a specific truncation of the env gene nor that of the nef gene appeared to be important in this regard.